DE1191371B - Process for the preparation of delta 1,4,12-13, 17-seco-androstatriene-3, 11-dione-17-caonic acid compounds and 11-keto-delta 1-dehydrotestolo-lactone compounds - Google Patents
Process for the preparation of delta 1,4,12-13, 17-seco-androstatriene-3, 11-dione-17-caonic acid compounds and 11-keto-delta 1-dehydrotestolo-lactone compoundsInfo
- Publication number
- DE1191371B DE1191371B DEO9180A DEO0009180A DE1191371B DE 1191371 B DE1191371 B DE 1191371B DE O9180 A DEO9180 A DE O9180A DE O0009180 A DEO0009180 A DE O0009180A DE 1191371 B DE1191371 B DE 1191371B
- Authority
- DE
- Germany
- Prior art keywords
- seco
- dione
- androstatriene
- keto
- compounds
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000002360 preparation method Methods 0.000 title claims description 16
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- 238000000034 method Methods 0.000 title claims description 11
- 150000001875 compounds Chemical class 0.000 title description 15
- 239000002253 acid Substances 0.000 title description 6
- -1 testololactone compound Chemical class 0.000 claims description 16
- 241000908271 Ilyonectria destructans Species 0.000 claims description 8
- 241000228153 Penicillium citrinum Species 0.000 claims description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 7
- 125000005843 halogen group Chemical group 0.000 claims description 4
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- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- BLCAJJQPGLGJDA-DVFHKXEWSA-N (8s,9s,10r,13s,14s,17s)-17-acetyl-10,13-dimethyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthrene-1,3-dione Chemical compound C1CC2=CC(=O)CC(=O)[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 BLCAJJQPGLGJDA-DVFHKXEWSA-N 0.000 claims description 2
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- CNIXJDVUMXTEKX-UHFFFAOYSA-N Testololactone Natural products O=C1CCC2(C)C3CCC(C)(OC(=O)CC4)C4C3CCC2=C1 CNIXJDVUMXTEKX-UHFFFAOYSA-N 0.000 claims description 2
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- VMPHSYLJUKZBJJ-UHFFFAOYSA-N trilaurin Chemical compound CCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCC)COC(=O)CCCCCCCCCCC VMPHSYLJUKZBJJ-UHFFFAOYSA-N 0.000 description 2
- PVNIQBQSYATKKL-UHFFFAOYSA-N tripalmitin Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCC PVNIQBQSYATKKL-UHFFFAOYSA-N 0.000 description 2
- DCXXMTOCNZCJGO-UHFFFAOYSA-N tristearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCCCC DCXXMTOCNZCJGO-UHFFFAOYSA-N 0.000 description 2
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- 235000021313 oleic acid Nutrition 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 239000002540 palm oil Substances 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 150000003146 progesterones Chemical class 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000004455 soybean meal Substances 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 239000003760 tallow Substances 0.000 description 1
- PHYFQTYBJUILEZ-IUPFWZBJSA-N triolein Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(OC(=O)CCCCCCC\C=C/CCCCCCCC)COC(=O)CCCCCCC\C=C/CCCCCCCC PHYFQTYBJUILEZ-IUPFWZBJSA-N 0.000 description 1
- 229940117972 triolein Drugs 0.000 description 1
- 229960001947 tripalmitin Drugs 0.000 description 1
- 238000009423 ventilation Methods 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J73/00—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/40—Unsaturated compounds
- C07C59/76—Unsaturated compounds containing keto groups
- C07C59/80—Unsaturated compounds containing keto groups containing rings other than six-membered aromatic rings
- C07C59/82—Unsaturated compounds containing keto groups containing rings other than six-membered aromatic rings the keto group being part of a ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/40—Unsaturated compounds
- C07C59/76—Unsaturated compounds containing keto groups
- C07C59/88—Unsaturated compounds containing keto groups containing halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/78—Ring systems having three or more relevant rings
- C07D311/80—Dibenzopyrans; Hydrogenated dibenzopyrans
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J73/00—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms
- C07J73/001—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom
- C07J73/003—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom by oxygen as hetero atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J75/00—Processes for the preparation of steroids in general
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/02—Ortho- or ortho- and peri-condensed systems
- C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
- C07C2603/22—Ortho- or ortho- and peri-condensed systems containing three rings containing only six-membered rings
- C07C2603/26—Phenanthrenes; Hydrogenated phenanthrenes
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S435/00—Chemistry: molecular biology and microbiology
- Y10S435/8215—Microorganisms
- Y10S435/822—Microorganisms using bacteria or actinomycetales
- Y10S435/872—Nocardia
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S435/00—Chemistry: molecular biology and microbiology
- Y10S435/8215—Microorganisms
- Y10S435/911—Microorganisms using fungi
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S435/00—Chemistry: molecular biology and microbiology
- Y10S435/8215—Microorganisms
- Y10S435/911—Microorganisms using fungi
- Y10S435/933—Penicillium
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
Verfahren zur Herstellung von #1,4,12-13,17-seco-Androstatrien-3, 1 i-dion-17-carbonsäure-Verbindungen und ll-Keto-Xl-dehydrotestololacton-Verbindungen Die Erfindung betrifft ein Verfahren zur Herstellung neuer Testololactone und seco-Androstatriencarbonsäure-Verbindungen.Process for the preparation of # 1,4,12-13,17-seco-androstatriene-3, 1 i-dione-17-carboxylic acid compounds and II-keto-Xl-dehydrotestololactone compounds The invention relates to a process for the preparation of new testololactones and seco-androstatrienecarboxylic acid compounds.
Die erfindungsgemäß herstellbaren Endprodukte haben die allgemeine Formel in der X ein Wasserstoffatom oder ein Halogenatom, vorzugsweise ein Wasserstoffatom oder ein Fluoratom, und R ein Wasserstoffatom oder ein Kohlenwasserstoffrest mit weniger als 10 Kohlenstoffatomen ist, z. B. ein niedrigmolekularer Alkylrest, wie der Methyl-, Äthyl-, Propyl-, Butyl-, Hexyl- oder Octylrest, ein monocyclischer Aralkylrest, wie der Benzyl-, Phenäthyl-, 3-Phenylpropyl-, 4-Phenylbutyl- oder der o-, m- oder p-Tolyläthylrest, ein monocyclischer Arylrest, ein Cycloalkyl- oder Cycloalkenylrest, ein durch einen Cycloalkylrest substituierter niedrigmolekularer Alkylrest, ein niedrigmolekularer Alkenylrest oder ein durch einen monocyclischen Arylrest substituierter niedrigmolekularer Alkenylrest.The end products which can be prepared according to the invention have the general formula in which X is a hydrogen atom or a halogen atom, preferably a hydrogen atom or a fluorine atom, and R is a hydrogen atom or a hydrocarbon radical having fewer than 10 carbon atoms, e.g. B. a low molecular weight alkyl radical, such as methyl, ethyl, propyl, butyl, hexyl or octyl radical, a monocyclic aralkyl radical, such as benzyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl or the o- , m- or p-tolylethyl radical, a monocyclic aryl radical, a cycloalkyl or cycloalkenyl radical, a low molecular weight alkyl radical substituted by a cycloalkyl radical, a low molecular weight alkenyl radical or a low molecular weight alkenyl radical substituted by a monocyclic aryl radical.
Das erfindungsgemäße Verfahren ist dadurch gekennzeichnet, daß man a) ein 11 -Ketoprogesteron der allgemeinen Formel I in der X ein Wasserstoffatom oder ein Halogenatom bedeutet, mit den Enzymen von Cylindrocarpon radicicola behandelt und gegebenenfalls die erhaltene #1,4,12-13,17-seco-Androstatrien-3,11-dion-17-carbonsäure in an sich bekannter Weise verestert oder b) die gleichzeitig erhaltene Testololactonverbindung der allgemeinen Formel 1 b durch Behandlung mit einer starken Base in die entsprechende seco-Androstatriencarbonsäure-Verbindung der allgemeinen Formedia überführt oder c) die Progesteronverbindung der allgemeinen Formel I mit Hilfe von Penicillium citrinum bebrütet und das erhaltene 1 1-Ketotestololacton in an sich bekannter Weise mikrobiologisch oder auf chemischem Wege in 1(2)-Stellung dehydriert.The process according to the invention is characterized in that a) an 11-ketoprogesterone of the general formula I is used in which X denotes a hydrogen atom or a halogen atom, treated with the enzymes of Cylindrocarpon radicicola and optionally the # 1,4,12-13,17-seco-androstatriene-3,11-dione-17-carboxylic acid obtained in a manner known per se esterified or b) the testololactone compound of the general formula 1b obtained at the same time is converted into the corresponding seco-androstatriencarboxylic acid compound of the general formula I by treatment with a strong base or c) the progesterone compound of the general formula I is incubated with the help of Penicillium citrinum and the 1 1-ketotestololactone is microbiologically or chemically dehydrated in a known manner in the 1 (2) position.
Zur Durchführung des erfindungsgemäßen Verfahrens wird entweder ll-Ketoprogesteron oder ein 9α-Halogen-11-ketoprogesteron als Steroidsubstrat verwendet, d. h., das Steroid wird einer wachsenden Kultur von Cylindrocarpon radicicola entweder während der Bebrütung zugesetzt oder dem Nährmedium vor der Beimpfung einverleibt. Bei Verwendung von ll-Ketoprogesteron, 9N-Jod-ll-ketoprogesteron oder 9a-Brom- 11 -ketoprogesteron als Substrat erhält man die 1,4,1213,1 7-seco-Androstatrien-3,11-dion-17-carbonsãure als Produkt. Wenn man jedoch als Substrat 9a-Fluor-1 1-ketoprogesteron verwendet, erhält man 9α-Fluor-#1,4,12-13,17-seco-androstatrien-3,11-dion-17-carbonsäure, und 9α-Chlor-11-ketoprogesteron liefert die 9α-Chlor-#1,4,12-13, 17-seco-androstatrien-3,1 l-dion-17-carbonsäure. Either II-ketoprogesterone is used to carry out the process according to the invention or using a 9α-halo-11-ketoprogesterone as a steroid substrate, d. H., the steroid is made from a growing culture of either Cylindrocarpon radicicola added during incubation or incorporated into the nutrient medium before inoculation. When using II-ketoprogesterone, 9N-iodine-II-ketoprogesterone or 9a-bromo-11-ketoprogesterone is obtained as substrate, 1,4,1213,1 7-seco-androstatriene-3,11-dione-17-carboxylic acid as a product. However, if one uses 9a-fluoro-1 1-ketoprogesterone as substrate, 9α-fluoro- # 1,4,12-13,17-seco-androstatriene-3,11-dione-17-carboxylic acid is obtained, and 9α-chloro-11-ketoprogesterone provides the 9α-chloro # 1,4,12-13, 17-seco-androstatriene-3,1 l-dione-17-carboxylic acid.
Diese freien Säuren können in üblicher Weise in ihre Ester umgewandelt werden, z. B. durch Behandlung mit dem gewünschten Alkohol in Gegenwart eines Veresterungskatalysators, oder für die Herstellung eines niedrigmolekularen Alkylesters durch Behandlung mit einem niedrigmolekularen Diazoalkan, wie Diazomethan. These free acids can be converted into their esters in the usual way be e.g. B. by treatment with the desired alcohol in the presence of an esterification catalyst, or for the preparation of a low molecular weight alkyl ester by treatment with a low molecular weight diazoalkane such as diazomethane.
Die erfindungsgemãß herstellbaren seco-Androstatriencarbonsäureverbindungen sind physiologisch aktive Stoffe, welche die Eiweißsynthese fördern (anabolische Aktivität). Die Verbindungen können daher an Stelle bekannter anabolisch wirkender Steroide verwendet und entweder peroral oder parenteral zur Behandlung von postoperativem Schock und anderen Zuständen verabreicht werden, bei denen Gewebedegeneration erfolgte. Die Verbindungen werden für diese Verabreichung in gleicher Form zu Arzneipräparaten verarbeitet, wie z. B. Testosteron, wobei die Konzentration und/oder die Dosis von der Aktivität der jeweiligen Verbindung abhängt. The seco-androstatrienecarboxylic acid compounds which can be prepared according to the invention are physiologically active substances that promote protein synthesis (anabolic Activity). The compounds can therefore act in place of known anabolic agents Steroids are used and either orally or parenterally for post-operative treatment Shock and other conditions where tissue degeneration has occurred. The compounds are used in the same form as medicinal preparations for this administration processed, such as B. Testosterone, the concentration and / or dose of depends on the activity of the respective connection.
Wie oben bereits bemerkt, erhält man neben den seco-Androstantriencarbonsäuren unter Verwendung von Cylindrocarpon radicicola als Mikroorganismus 11 -Keto- 1 -dehydrotestololacton, 9a-Chlor- 11 -ketol-dehydrotestololacton oder 9N-Fluor-l l-keto-l-dehydrotestololacton, wenn man als Steroidsubstrat ein ll-Ketoprogesteron (oder 9x-Jod-ll-ketoprogesteron oder 9a-Brom- 11 -ketoprogesteron) oder 9eu-Chlor-oder 9a-Fluor-ll-ketoprogesteron verwendet. As noted above, in addition to the seco-androstantriene carboxylic acids using Cylindrocarpon radicicola as the microorganism 11 -Keto- 1 -dehydrotestololactone, 9a-chloro-11-ketol-dehydrotestololactone or 9N-fluoro-l-l-keto-l-dehydrotestololactone, if the steroid substrate is II-ketoprogesterone (or 9x-iodine-II-ketoprogesterone or 9a-bromo-11-ketoprogesterone) or 9eu-chloro- or 9a-fluoro-II-ketoprogesterone used.
Diese 1 l-Keto-l-dehydrotestololactone sind bisher nicht bekannte Verbindungen, welche durch Behandlung mit einer starken Base, z. B. einem Alkalihydroxyd, wie Kalium- oder Natriumhydroxyd, in die entsprechenden erfindungsgemäß herstellbaren seco-Androstatriencarbonsäuren umgewandelt werden können. These 1 l-keto-l-dehydrotestololactones are not previously known Compounds obtained by treatment with a strong base, e.g. B. an alkali hydroxide, such as potassium or sodium hydroxide, into the corresponding preparable according to the invention seco-Androstatriencarbonsäuren can be converted.
Die Umsetzung wird vorzugsweise bei erhöhter Temperatur durchgeführt.The reaction is preferably carried out at an elevated temperature.
Die erfindungsgemäß herstellbaren ll-Keto-l-dehydrotestololacton-Verbindungen können auch nach einem zweistufigen Verfahren hergestellt werden. In der ersten Stufe wird ll-Ketoprogesteron, 9-Chlorll-ketoprogesteron oder 9a-Fluor- 11 -ketoprogesteron mit Penicillium citrinum behandelt, wobei ll-Ketotestololacton, 9 a - Chlor - 11 -ketotestololacton bzw. The II-keto-l-dehydrotestololactone compounds which can be prepared according to the invention can also be made by a two-step process. In the first Stage becomes ll-ketoprogesterone, 9-chloroII-ketoprogesterone or 9a-fluoro-11-ketoprogesterone treated with Penicillium citrinum, with ll-ketotestololactone, 9 a - chlorine - 11 -ketotestololactone or
9a-Fluor-1 l-ketotestololacton entsteht. Diese 1 l-Ketotestololactone sind ebenfalls bisher nicht bekannte Verbindungen.9a-fluoro-1 l-ketotestololactone is formed. This 1 l-ketotestololactone are also previously unknown compounds.
Die Umwandlung der Progesteronverbindungen erfolgt, indem man entweder das Steroid mit Sauerstoff und den Enzymen der nicht proliferierenden Zellen von Penicillium citrinum in einem wäßrigen Medium zusammenbringt, oder vorzugsweise, indem man das Steroid in einer belüfteten Kultur von Penicillium citrinum fermentiert. The conversion of the progesterone compounds is done by either the steroid with oxygen and the enzymes of the non-proliferating cells of Bringing Penicillium citrinum together in an aqueous medium, or preferably, by fermenting the steroid in an aerated culture of Penicillium citrinum.
Bei Verwendung einer belüfteten Kultur wird die Oxydation in Gegenwart von Penicillium citrinum bewirkt, indem man das Steroid der Kultur während der Bebrütungsperiode zusetzt oder indem man es dem Nährmedium vor der Beimpfung einverleibt. In jedem Fall müssen im Gärmedium zur Wachstumsförderung assimilierbare Stickstoffquellen und als Energiequelle kohlenstoffhaltige Verbindungen vorliegen. Während der Oxydation muß auch für ausreichende Luftzufuhr gesorgt werden, beispielsweise indem man in üblicher Weise eine große Oberfläche des Mediums der Luft aussetzt oder eine Submerskultur belüftet. When using an aerated culture, the oxidation is in the presence of Penicillium citrinum is effected by adding the steroid to the culture during the incubation period or by adding it to the nutrient medium before inoculation. In each Case must be in the fermentation medium to promote growth assimilable nitrogen sources and carbonaceous compounds are present as an energy source. During the oxidation adequate ventilation must also be ensured, for example by placing in usually exposing a large surface area of the medium to air or a submerged culture ventilated.
Im allgemeinen sind die Bedingungen der erfindungsgemäßen Züchtung von Penicillium citrinum, mit Ausnahme der Einverleibung des Steroids, die gleichen, wie die zur Züchtung anderer Stoffwechselprodukte liefernder Mikroorganismen. Somit enthält das Nährmedium im wesentlichen assimilierbare Stickstoffquellen zum Wachstum und Kohlenstoffquellen zur Energiezufuhr. In general, the conditions of cultivation according to the invention are of Penicillium citrinum, with the exception of the incorporation of the steroid, the same, like the microorganisms that produce other metabolic products. Consequently the nutrient medium contains essentially assimilable sources of nitrogen for growth and sources of carbon for energy input.
Als Stickstoffquellen können organische Stoffe, z. B. Organic substances, e.g. B.
Sojabohnenmehl, Maisquellwasser, Fleischextrakt und/oder lösliche Destillationsrückstände oder synthetische Stoffe, d. h. einfache synthetisierbare organische oder anorganische Verbindungen, wie Ammoniumsalze, Alkalinitrate, Aminosäuren, Harnstoff oder Thioharnstoff, verwendet werden.Soybean meal, corn steep liquor, meat extract and / or soluble Distillation residues or synthetic substances, d. H. easy synthesizable organic or inorganic compounds such as ammonium salts, alkali nitrates, amino acids, Urea or thiourea can be used.
Als energieliefernde Stoffe werden Lipoide, insbesondere Fettsäuren mit mindestens 14 Kohlenstoffatomen, oder Fette oder deren Gemische verwendet. Beispiele für solche Fette sind Schmalzöl, Sojabohnenöl, Leinsamenöl, Baumwollsamenöl, Erdnußöl, Kokosnußöl, Maisöl, Castoröl, Sesamöl, rohes Palmöl, Hammeltalg, Spermöl, Olivenöl, Tristearin, Tripalmitin, Triolein und Trilaurin. Beispiele für Fettsäuren sind Stearinsäure, Palmitinsäure, Ölsäure, Linolensäure und Myristinsäure. Lipoids, especially fatty acids, are used as energy-supplying substances with at least 14 carbon atoms, or fats or their mixtures are used. Examples for such fats are lard oil, soybean oil, flaxseed oil, cottonseed oil, peanut oil, Coconut oil, corn oil, castor oil, sesame oil, raw palm oil, mutton tallow, sperm oil, olive oil, Tristearin, tripalmitin, triolein and trilaurin. Examples of fatty acids are stearic acid, Palmitic acid, oleic acid, linolenic acid and myristic acid.
Es können auch andere kohlenstoffhaltige Verbindungen verwendet werden, wie Glycerin, Glucose, Fructose, Rohrzucker, Lactose, Maltose, Stärken, Molke u. dgl. Diese Stoffe können entweder in gereinigtem Zustand oder als Konzentrate, z. B. als Molkekonzentrat, Mais-, Weizen- oder Gerstenmaische oder als Gemische der vorstehend genannten Stoffe verwendet werden. Das Steroid wird dem Gärmedium jedoch nicht als Energiequelle, sondern als Ausgangsverbindung zugesetzt. Other carbonaceous compounds can also be used, such as glycerine, glucose, fructose, cane sugar, lactose, maltose, starches, whey and the like. Like. These substances can either in the purified state or as concentrates, eg. B. as whey concentrate, corn, wheat or barley mash or as mixtures of the substances mentioned above are used. The steroid is added to the fermentation medium, however not added as an energy source, but as a starting compound.
Die erfindungsgemäß hergestellten ll-Ketotestololactone werden anschließend in der 1(2)-Stellung entweder mikrobiologisch, z. B. mit einem bekannten, die 1-Stellung dehydrierenden Mikroorganismus, wie Nocardia restrictus, oder chemisch, z. B. durch Behandlung mit Selendioxyd oder 2,3-Dichlor-5,6-dicyanbenzochinon, zu den 11-Keto-1 -dehydrotestololactonen dehydriert. The II-ketotestololactones prepared according to the invention are then in the 1 (2) position either microbiologically, e.g. B. with a known, the 1-position dehydrating microorganism such as Nocardia restrictus, or chemically, e.g. B. by Treatment with selenium dioxide or 2,3-dichloro-5,6-dicyanobenzoquinone, to the 11-keto-1 -dehydrotestololactonen dehydrated.
Abgesehen von ihrer Verwendung als Zwischenprodukte sind die erfindungsgemäß herstellbaren 1 l-Ketotestololactone der allgemeinen Formel in welcher die 1(2)-Stellung gegebenenfalls eine Doppelbindung aufweist und X die oben angegebene Bedeutung besitzt, ebenfalls physiologisch aktive Stoffe, welche die Eiweißsynthese fördern (anabolische Aktivität), die somit an Stelle bekannter anabolisch wirkender Agentien zur Behandlung von Osteoporosis, Proteingewebeerschöpfung und chronischer Schwäche und Gewebeatrophie in der Geriatrie verwendet werden können. Zu diesem Zweck werden die Verbindungen entweder peroral oder parenteral zur Behandlung von postoperativem Schock und anderen Zuständen verabreicht, bei denen Gewebedegeneration erfolgte. Die Verbindungen werden für diese Verabreichung in gleicher Form zu Arzneipräparaten verarbeitet, wie z. B. Testosteron, wobei die Konzentration und/oder die Dosis von der Aktivität der jeweiligen Verbindung abhängt.Apart from their use as intermediates, the 1 l-ketotestololactones which can be prepared according to the invention are of the general formula in which the 1 (2) position optionally has a double bond and X has the meaning given above, also physiologically active substances that promote protein synthesis (anabolic activity), which are thus in place of known anabolic agents for the treatment of osteoporosis, protein tissue exhaustion and chronic weakness and tissue atrophy can be used in geriatrics. For this purpose, the compounds are administered either orally or parenterally for the treatment of post-operative shock and other conditions in which tissue degeneration has occurred. The compounds are processed into medicinal preparations for this administration in the same form, such as. B. testosterone, the concentration and / or the dose depending on the activity of the respective compound.
Die nachstehenden Beispiele erläutern das erfindungsgemäße Verfahren. The following examples illustrate the process according to the invention.
Beispiel 1 Herstellung von 9α-Fluor-1 l-keto-l-dehydrotestololacton und 9α-Fluor-#1,4,12-13,17-seco-androstatrien-3,11-dion-17-carbonsäure Ein Oberflächenwachstum einer 3 Wochen alten Schrägagarkultur von Cylindrocarpon radicicola (ATCC 11011) wird in 2,5 ml einer wäßrigen 0,01 %igen Natriumlaurylsulfatlösung suspendiert. Die Schrägagars enthalten als Nährmedium (A) 10 g Glucose, 2,5 g »Difco«-Hefeextrakt. i g K2HPO4, 20 g Agar und destilliertes Wasser ad 11. l-mi-Anteile der Suspension werden zur Beimpfung von zwei 250 ml fassenden Erlenmeyerkolben verwendet, die jeweils 50 ml des folgenden sterilisierten Nährmediums (B) enthalten: 10 g Dextrose, 6 g Maisquellwasser, 3 g NH4H2PO4, 2,5 g »Difco«-Hefeextrakt, 2,5 g CaCl2 und destilliertes Wasser ad 1 1. Example 1 Preparation of 9α-fluoro-1 l-keto-l-dehydrotestololactone and 9α-fluoro- # 1,4,12-13,17-seco-androstatriene-3,11-dione-17-carboxylic acid A Surface growth of a 3 week old agar slant culture of Cylindrocarpon radicicola (ATCC 11011) is dissolved in 2.5 ml of an aqueous 0.01% sodium lauryl sulfate solution suspended. The agar slants contain 10 g glucose and 2.5 g "Difco" yeast extract as nutrient medium (A). i g K2HPO4, 20 g agar and distilled water ad 11.1 ml portions of the suspension are used to inoculate two 250 ml Erlenmeyer flasks, each Contain 50 ml of the following sterilized nutrient medium (B): 10 g dextrose, 6 g Corn steep water, 3 g NH4H2PO4, 2.5 g "Difco" yeast extract, 2.5 g CaCl2 and distilled Water ad 1 1.
Nach 48stündiger Bebrütung bei 25"C auf einer Rotationsschüttelmaschine mit' 280 U/min, 50,8 mm Radius, werden 1 Ovolumprozentige Übertragungen auf zwölf 250-ml-Ertenmeyerkolben durchgeführt, die jeweils 50 ml frisches sterilisiertes Nährmedium (B) enthalten. Diese Erlenmeyerkolben werden unter den vorstehend beschriebenen Bedingungen 24 Stunden bebrütet. Danach wird eine weitere 10volumprozentige Übertragung auf weitere hundert 250-ml-Erlenmeyerkolben durchgeführt, die jeweils 50 ml frisch sterilisiertes Nährmedium (B) enthalten. Jeder Erlenmeyerkolben wird mit 0,25 ml einer sterilen, 60 mg/ml enthaltenden Lösung von 9r-Fluor-l l-ketoprogesteron in N,N-Dimethylformamid versetzt. Somit enthält das Medium 300 y/ml Steroid. Nach 48stündiger Bebrütung wird der Inhalt der Erlenmeyerkolben vereinigt und durch ein Seitzklärfilter filtriert. Die Kolben, das Mycel und das Klärfilter werden mit 50-ml-Anteilen warmem Wasser gewaschen. Die vereinigten Filtrate und Waschlösungen, die einen pH-Wert von 8,2 haben, werden mit Essigsäure auf pH 4 angesäuert und dreimal mit 2-1-Anteilen Chloroform extrahiert. Die vereinigten Chloroformextrakte werden hierauf zweimal mit 3-1-Anteilen Wasser gewaschen und anschließend im Vakuum zur Trockene eingedampft.After 48 hours of incubation at 25 "C on a rotary shaker at '280 rpm, 50.8 mm radius, there are 10 volume percent transfers on twelve 250 ml Ertenmeyer flasks, each 50 ml fresh sterilized Contain nutrient medium (B). These Erlenmeyer flasks are among those described above Conditions incubated for 24 hours. Then there is another 10 volume percent transfer carried out on another hundred 250 ml Erlenmeyer flasks, each 50 ml fresh Contain sterilized nutrient medium (B). Each Erlenmeyer flask is 0.25 ml a sterile, 60 mg / ml solution of 9r-fluoro-l-ketoprogesterone in N, N-dimethylformamide added. Thus the medium contains 300 µg / ml steroid. After 48 hours Incubation, the contents of the Erlenmeyer flasks are combined and passed through a Seitz clarifier filtered. The flasks, mycelium and clearing filter are warmed with 50 ml portions Water washed. The combined filtrates and washing solutions that have a pH of 8.2 are acidified to pH 4 with acetic acid and three times with 2-1 parts Chloroform extracted. The combined chloroform extracts are then used twice washed with 3-1 parts of water and then evaporated to dryness in vacuo.
Der Rückstand wird in 200 ml Äthylacetat gelöst und mit zwei 100-ml-Anteilen 5%iger Natriumbicarbonatlösung extrahiert. Die Äthylacetatlösung wird hierauf mit Wasser gewaschen, über Natriumsulfat getrocknet und im Vakuum zur Trockene eingedampft. Nach Umkristallisation des Rückstandes aus einer Mischung von Aceton Hexan erhält man 100 mg 9A-Fluor-11-keto-#¹-dehydrotestololacton vom Fp. 217 bis 220°C; [α]D22 = +28,5° (CHCl3); #maxC2H5OH = 234 mµ (# = 16000); #max0,005% KOH in C2H3OH = 241 mµ (e = 27400); #maxNujol = 5,80, 5,86, 6,00, 6,13, 6,22 µ; E1 2DMF 1,19 V (gegen Hg-Anode).The residue is dissolved in 200 ml of ethyl acetate and mixed with two 100 ml portions 5% sodium bicarbonate solution extracted. The ethyl acetate solution is then with Washed water, dried over sodium sulfate and evaporated to dryness in vacuo. After recrystallization of the residue from a mixture of acetone, hexane is obtained 100 mg of 9A-fluoro-11-keto- # 1 -dehydrotestololactone of melting point 217 to 220 ° C .; [α] D22 = + 28.5 ° (CHCl3); # maxC2H5OH = 234 mµ (# = 16000); # max 0.005% KOH in C2H3OH = 241 mµ (e = 27400); #maxNujol = 5.80, 5.86, 6.00, 6.13, 6.22 µ; E1 2DMF 1.19 V (against Mercury anode).
C19H21O4F (332,48): Berechnet ... C 68,66°/o, H 6,37%; gefunden ... C 68,95°/Os H 6,120/o Die Natriumbicarbonatextrakte werden mit 2 n-Salzsäure angesäuert und mit drei 100-ml-Anteilen Chloroform extrahiert. Die vereinigten Chloroformextrakte werden mit Wasser gewaschen und im Vakuum zur Trockene eingedampft. Die Umkristallisation des Rückstands aus einer Mischung von Aceton und Hexan liefert 910 mg 9α-Fluor-#1,4,12-13,17-secoandrostatrien-3,11-dion-17-carbonsäure vom Fp. 217 bis 220°C.C19H21O4F (332.48): Calculated ... C 68.66%, H 6.37%; found ... C 68.95 ° / Os H 6.120 / o The sodium bicarbonate extracts are acidified with 2N hydrochloric acid and extracted with three 100 ml portions of chloroform. The combined chloroform extracts are washed with water and evaporated to dryness in vacuo. The recrystallization the residue from a mixture of acetone and hexane yields 910 mg of 9α-fluoro- # 1,4,12-13,17-secoandrostatriene-3,11-dione-17-carboxylic acid from m.p. 217 to 220 ° C.
[α]D22 = -46,5° (CHCl3); #maxC2H5OH = 240 mµ (# = 28 500); #maxNujol = 5,80, 6,02, 6,12, 6,24 µ; E1 2DMF = 1,14 V (gegen Hg-Anode).[α] 22 D = -46.5 ° (CHCl3); # maxC2H5OH = 240 mµ (# = 28,500); #maxNujol = 5.80, 6.02, 6.12, 6.24 µ; E1 2DMF = 1.14 V (against Hg anode).
C19H21O4F (332,48): Berechnet... C 68,66%, H 6,37%; gefunden ... C 69,03 0/o, H 6,21 0/o.C19H21O4F (332.48): Calculated ... C 68.66%, H 6.37%; found ... C 69.03 0 / o, H 6.21 0 / o.
Neutralisationsäquivalent 347. Neutralization equivalent 347.
Beispiel 2 Es wird nach dem Verfahren des Beispiels 1 gearbeitet, jedoch wird die Endstufe in 2-1-Kolben durchgeführt, die 500 ml Nährmedium enthalten. Example 2 The procedure of Example 1 is followed, however, the final stage is carried out in 2-1 flasks containing 500 ml of nutrient medium.
Der pH-Wert wird täglich mit Salzsäure auf einen Wert wenig unter pH 7 eingestellt. Die vereinigten Filtrate und Waschlösungen werden hierauf gemäß Beispiel 1 extrahiert und in die sauren und neutralen Fraktionen zerlegt. Nach Umkristallisation erhält man 360 mg 9α-Fluor-#1,4,12-13,17-seco-androstatrien-3,11-dion-17-carbonsäure vom Fp. 217 bis 220°C und 510 mg 9α-Fluor-11-keto-#¹-dehydrotestololacton vom Fp. 217 bis 220°C.The pH value is reduced daily with hydrochloric acid to a value a little below pH 7 adjusted. The combined filtrates and wash solutions are then appropriately Example 1 extracted and broken down into the acidic and neutral fractions. After recrystallization 360 mg of 9α-fluoro- # 1,4,12-13,17-seco-androstatriene-3,11-dione-17-carboxylic acid are obtained of m.p. 217 to 220 ° C and 510 mg of 9α-fluoro-11-keto- # 1 -dehydrotestololactone from m.p. 217 to 220 ° C.
Beispiel 3 Herstellung von 11-Keto-#¹-dehydrotestololacton und #1,4,12-13,17-seco-Androstatrien-3,11-dion-17-carbonsäure Die Vergärung und die Extraktion werden gemäß Beispiel 1 durchgeführt, jedoch wird ll-Ketoprogesteron an Stelle von 9α-Fluor-11-ketoprogesteron verwendet. Man erhält 320 mg 11-Keto-#¹-dehydrotestololacton vom Fp. 196 bis 198°C. Example 3 Preparation of 11-keto- # 1 -dehydrotestololactone and # 1,4,12-13,17-seco-androstatriene-3,11-dione-17-carboxylic acid The fermentation and the extraction are carried out according to Example 1, however II-ketoprogesterone used in place of 9α-fluoro-11-ketoprogesterone. Man receives 320 mg of 11-keto- # 1 -dehydrotestololactone with a melting point of 196 ° to 198 ° C.
[α]D22 = +79,0° (CHCl3); #maxC2H5OH = 238 mµ (# = 15 900); #max0,05% KOH in C2HsOH = 238 mµ (e = 25 600); #maxNujol = 5,74, 5,83, 6,00, 6,13, 6,22 µ; C19H2204 (314,37): Berechnet ... C 72,59%, H 7,05 0/o; gefunden ... C 72,51 0/o, H 7,240/o; und 363 mg #1,4,12-13,17-seco-Androstatrien-3,11-dion-17-carbonsäure vom Fp. 167 bis 169°C; [α]D22 = #0° (CHCl3); #maxC2H3OH = 238 mµ (# = 29 800); #maxNujol = 5,81 6,00, 6,02 (Schulter), 6,22 (Schulter), 6,24 ia.[α] 22 D = + 79.0 ° (CHCl3); # maxC2H5OH = 238 mµ (# = 15,900); # max0.05% KOH in C2HsOH = 238 mµ (e = 25,600); #maxNujol = 5.74, 5.83, 6.00, 6.13, 6.22 µ; C19H2204 (314.37): Calculated ... C 72.59%, H 7.05%; found ... C 72.51 0 / o, H 7.240 / o; and 363 mg of # 1,4,12-13,17-seco-androstatriene-3,11-dione-17-carboxylic acid from m.p. 167 to 169 ° C; [α] 22 D = # 0 ° (CHCl3); # maxC2H3OH = 238 mµ (# = 29,800); #maxNujol = 5.81 6.00, 6.02 (shoulder), 6.22 (shoulder), 6.24 ia.
Beispiel 4 Die Vergärung wird gemäß Beispiel 1 durchgeführt und als Substrat 9x-Brom-l l-ketoprogesteron verwendet. Die Endstufe der Vergärung wird in 2-1-Kolben durchgeführt, die 500 ml Nährmedium enthalten. Die Produkte werden gemäß Beispiel 1 in saure und neutrale Fraktionen aufgetrennt. Man erhält etwa 500 mg 11-Keto-#¹-dehydrotestololacton und etwa 200 mg #1,4,12-13,17-seco-Androstatrien-3,1 l-dion-17-carbonsäure, die mit den Produkten des Beispiels 4 identisch sind. Example 4 The fermentation is carried out according to Example 1 and as Substrate 9x-bromo-l-ketoprogesterone used. The final stage of fermentation will be carried out in 2-1 flasks containing 500 ml of nutrient medium. the Products are separated according to Example 1 into acidic and neutral fractions. Man receives about 500 mg of 11-keto- # 1 -dehydrotestololactone and about 200 mg of # 1,4,12-13,17-seco-androstatriene-3,1 l-dione-17-carboxylic acid, which are identical to the products of Example 4.
In ähnlicher Weise liefert 9α-Jod-1 l-ketoprogesteron das 11-Keto-#¹-dehydrotestololacton vom Fp. 196 bis 198°C und die #1,4,13-13,17-seco-Androstatrien-3,11-dion-17-carbonsäure vom Fp. 167 bis 169°C. Similarly, 9α-iodine-1 l-ketoprogesterone provides the 11-keto- # 1 -dehydrotestololactone of m.p. 196 to 198 ° C and the # 1,4,13-13,17-seco-androstatriene-3,11-dione-17-carboxylic acid from m.p. 167 to 169 ° C.
Beispiel 5 Herstellung von 9α-Fluor-#1,4,12-13,17-seco-androstatrien-3,11-dion-17-carbonsäure 60 mg 9α-Fluor-11-keto-#¹-dehydrotestololacton werden in 5 ml einer 50/gen Lösung von Kaliumhydroxyd in Methanol gelöst und auf dem Dampfbad 5 Minuten erwärmt. Die Lösung wird hierauf abgekühlt, mit Essigsäure neutralisiert, mit Wasser verdünnt und mit Äther extrahiert. Der Äther wird hierauf mit 5%iger Natriumbicarbonatlösung extrahiert. Die Natriumbicarbonatlösung wird angesäuert und mit Äther extrahiert. Der Ätherextrakt wird getrocknet, zur Trockene eingedampft und der Rückstand aus einer Mischung von Aceton und Hexan umkristallisiert. Man erhält die 9α-Fluor-#1,4,12-13,17-seco-androstatrien-3,11-dion-17-carbonsäurevom Fp. 217 bis 220°C. Example 5 Preparation of 9α-fluoro- # 1,4,12-13,17-seco-androstatriene-3,11-dione-17-carboxylic acid 60 mg of 9α-fluoro-11-keto- # ¹-dehydrotestololactone are in 5 ml of a 50 / gen Solution of potassium hydroxide dissolved in methanol and heated on the steam bath for 5 minutes. The solution is then cooled, neutralized with acetic acid and diluted with water and extracted with ether. The ether is then mixed with 5% sodium bicarbonate solution extracted. The sodium bicarbonate solution is acidified and extracted with ether. The ether extract is dried, evaporated to dryness and the residue is removed a mixture of acetone and hexane recrystallized. The 9α-fluoro- # 1,4,12-13,17-seco-androstatriene-3,11-dione-17-carboxylic acid is obtained from Mp 217-220 ° C.
Cl9H2l04F (332,48): Berechnet ... C 68,64°/o, H 6,37%, F 5,71 0/o; gefunden ... C 67,780/o, H 6,81%, F 5,6°/o-Beispiel 6 Herstellung von #1,4,12-13,1 7-seco-Androstatrien-3,11 -dion-1 7carbonsäure Nach dem Verfahren des Beispiels 5, jedoch unter Verwendung einer äquivalenten Menge 11-Keto-#¹-dehydrotestololacton an Stelle von 9α-Fluor-11 -keto-Zl ¹-dehydrotestololacton, erhält man die #1,4,12-13,17-seco-Androstatrien-3,11-dion-17-carbonsäure vom Fp. 167 bis 169°C.Cl9H2104F (332.48): Calculated ... C 68.64%, H 6.37%, F 5.71%; Found ... C 67.780 / o, H 6.81%, F 5.6 ° / o Example 6 Preparation of # 1,4.12-13.1 7-seco-androstatriene-3,11-dione-17carboxylic acid Following the procedure of the example 5, but using an equivalent amount of 11-keto- # 1 -dehydrotestololactone instead of 9α-fluoro-11 -keto-Zl ¹-dehydrotestololactone, one obtains the # 1,4,12-13,17-seco-androstatriene-3,11-dione-17-carboxylic acid, mp 167-169 ° C.
Beispiel 7 Herstellung von 9α-Fluor-#1,4,12-13,17-seco-androstatrien-3,11-dion-17-carbonsäuremethylester Eine Suspension von 360 mg 9α-Fluor-#1,4,12-13,17-seco-androstatrien-3,11-dion-17-carbonsäure in 10 ml Methanol wird langsam unter Umschütteln mit einer Ätherlösung von Diazomethan versetzt, bis das Steroid gelöst ist und die gelbe Farbe des Diazomethans bestehenbleibt. Nach 30 Minuten Stehen bei Raumtemperatur wird die Lösung im Vakuum zur Trockene eingedampft und der Rückstand zwischen Äthylacetat und 3%iger Natriumbicarbonatlösung verteilt. Die Äthylacetatlösung wird gründlich mit Wasser gewaschen, über Natriumsulfat getrocknet und im Vakuum zur Trockene eingedampft. Die Chromatographie des Rückstands an neutralem Aluminiumoxyd (Woelm) und Eluierung mit Chloroform-Benzol (1: 9) liefert nach Umkristallisation aus einer Mischung von Aceton und Hexan etwa 200 mg 9α-Fluor-#1,4,12-13,77-seco-androstatrien-3,11-dion-17-carbonsäuremethylester vom Fp. 119 bis 121 °C; [α]D23 = -46,9° (CHCl3); #maxC2H,OH 239 mµ (e = 29 400); #maxNujol = = 5,80, 5,96 bis 6,01, 6,12, 6,21 , C20H23O4F (346,38): Berechnet ... C 69,34%, H 6,690/o, F 5,49o/o; gefunden ... C 69,50%, H 7,09%, F 5,53%. Example 7 Preparation of 9α-fluoro- # 1,4,12-13,17-seco-androstatriene-3,11-dione-17-carboxylic acid methyl ester A suspension of 360 mg of 9α-fluoro- # 1,4,12-13,17-seco-androstatriene-3,11-dione-17-carboxylic acid in 10 ml of methanol is slowly shaken with an ethereal solution of diazomethane until the steroid is dissolved and the yellow color of the diazomethane persists. After standing at room temperature for 30 minutes, the solution becomes dry in vacuo evaporated and the residue between ethyl acetate and 3% sodium bicarbonate solution distributed. The ethyl acetate solution is washed thoroughly with water over sodium sulfate dried and evaporated to dryness in vacuo. Chromatography of the residue on neutral aluminum oxide (Woelm) and elution with chloroform-benzene (1: 9) after recrystallization from a mixture of acetone and hexane, about 200 mg of methyl 9α-fluoro- # 1,4,12-13,77-seco-androstatriene-3,11-dione-17-carboxylate from fp. 119 to 121 ° C; [α] 23 D = -46.9 ° (CHCl3); # maxC2H, OH 239 mµ (e = 29 400); #maxNujol = = 5.80, 5.96-6.01, 6.12, 6.21, C20H23O4F (346.38): calculated ... C 69.34%, H 6.690 / o, F 5.49o / o; found ... C 69.50%, H 7.09%, F 5.53%.
Beispiel 8 Herstellung von 9α-Fluor-1 l-ketotestololacton Die Vergärung und Extraktion erfolgt gemäß Beispiel 1, jedoch wird eine Kultur von Penicillium citrinum (ATCC 8506) an Stelle von Cylindrocarpon radicicola verwendet. Nach Umkristallisation der neutralen Fraktion erhält man 667 mg 9α-Fluor-11 - ketostestololacton vom Fp. 193 bis 195° C; [α]D23 = +59,4°(CHCl3);#maxC2H5OH = 233 mµ(# = 17400); #maxNujol = 5,77, 6,00, 6,17 µ. Example 8 Preparation of 9α-fluoro-1 l-ketotestololactone Die Fermentation and extraction are carried out as in Example 1, but a culture of Penicillium is used citrinum (ATCC 8506) used in place of Cylindrocarpon radicicola. After recrystallization the neutral fraction gives 667 mg of 9α-fluoro-11-ketostestololactone from m.p. 193 to 195 ° C; [α] 23 D = + 59.4 ° (CHCl3); # maxC2H5OH = 233 mµ (# = 17400); #maxNujol = 5.77, 6.00, 6.17 µ.
Beispiel 9 Herstellung von 1 l-Ketotestololacton Die Vergärung und Extraktion erfolgt gemäß Beispiel 1, jedoch wird an Stelle von Cylindrocarpon radicicola eine Kultur von Penicillium citrinum (ATCC 8506) und an Stelle von 9α-Fluor-11-ketoprogesteron das ll-Ketoprogesteron verwendet. Man erhält 650 mg ll-Ketotestololacton vom Fp. 226 bis 228°C; [α]D22 = +121° (CHCl3); #maxC2H5OH = 237 mµ (# = 17 200); #max0,01 n-KOH in CH3OH = 238 mµ (# = 27 400); #maxNujol = 5,81, 5,84, 6,00, 6,17 µ. Example 9 Preparation of 1 l-ketotestololactone The fermentation and Extraction takes place as in Example 1, but instead of Cylindrocarpon radicicola a culture of Penicillium citrinum (ATCC 8506) and instead of 9α-fluoro-11-ketoprogesterone the ll-ketoprogesterone used. 650 mg of II-ketotestololactone with melting point are obtained. 226 to 228 ° C; [α] 22 D = + 121 ° (CHCl3); # maxC2H5OH = 237 mµ (# = 17,200); # max0.01 n-KOH in CH3OH = 238 mµ (# = 27,400); #maxNujol = 5.81, 5.84, 6.00, 6.17 µ.
C19H24O4 (316,38): Berechnet ... C 72,120/o, H 7s65°/o; gefunden ... C 72,26%, H 7,77 O/o.C19H24O4 (316.38): Calculated ... C 72.120 / o, H 7-65 ° / o; found ... C 72.26%, H 7.77 O / o.
Beispiel 10 Herstellung von 9α-Fluor-11-keto-#¹-dehydrotestololacton Die Vergärung erfolgt gemäß Beispiel 1, jedoch wird eine Kultur von Nocardia restrictus (Culture Collection, Rutgers Institute of Microbiology, Nr. 545) an Stelle von Cylindrocarpon radicicola verwendet. Example 10 Preparation of 9α-fluoro-11-keto- # 1 -dehydrotestololactone The fermentation takes place according to Example 1, but a culture of Nocardia restrictus (Culture Collection, Rutgers Institute of Microbiology, No. 545) in place of Cylindrocarpon radicicola used.
Als Substrat werden 200 mg 9x-Fluor-l l-ketotestololacton verwendet und in zwanzig 250-ml-Kolben verteilt. Nach 7l/2stündiger Vergärung wird die Gärbrühe abfiltriert, das Filter, die Kolben und das Mycel mit Wasser gewaschen und das vereinigte Filtrat und die Waschlösung (1,11) dreimal mit 300-ml-Anteilen Chloroform extrahiert. Die Chloroformextrakte werden veieinigt, mit Wasser gewaschen und im Vakuum .ur Trockene eingedampft. Nach Umkristallisation des Rückstands aus einer Mischung von Aceton und Hexan erhilt man 100 mg 9x-Fluor-11-keto-#¹-dehydrotestololactonvomFp.217bis220°C.200 mg of 9x-fluoro-l-ketotestololactone are used as substrate and divided into twenty 250 ml flasks. After fermentation for 7l / 2 hours, the fermentation broth becomes filtered off, the filter, the flasks and the mycelium washed with water and the combined The filtrate and the washing solution (1.11) were extracted three times with 300 ml portions of chloroform. The chloroform extracts are combined, washed with water and in vacuo .ur Evaporated dry. After recrystallization of the residue from a mixture of Acetone and hexane, 100 mg of 9x-fluoro-11-keto- # 1 -dehydrotestololactone, mp 217-220 ° C, are obtained.
Beispiel 11 Herstellung von 11-Keto-#¹-dehydrotestololacton Nach dem Verfahren des Beispiels 10, jedoch unter Verwendung von 11-Ketotestololacton an Stelle von 9α-Fluor-1 l-ketotestololacton erhält man das l l-Keto-Al-dehydrotestololacton vom Fp. 196 bis 198°C. Example 11 Preparation of 11-keto- # 1 -dehydrotestololactone According to the procedure of Example 10, but using 11-ketotestololactone instead of 9α-fluoro-1 l-ketotestololactone one obtains the l-keto-Al-dehydrotestololactone from m.p. 196 to 198 ° C.
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|---|---|---|---|---|
| US3278556A (en) * | 1964-02-03 | 1966-10-11 | Squibb & Sons Inc | Synthesis of steroids |
| CN119193433B (en) * | 2024-11-22 | 2025-03-18 | 中国科学院南京土壤研究所 | Nocardioides sp. NJF-4 and its application in biodefluorination of fluorinated alkyl compounds |
Family Cites Families (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2760966A (en) * | 1953-06-17 | 1956-08-28 | Monsanto Chemicals | Compounds for synthesizing steroids |
| GB792803A (en) * | 1953-08-21 | 1958-04-02 | Ciba Ltd | Oxidation products from compounds of the steroid series and process of making same |
| US2806038A (en) * | 1954-05-07 | 1957-09-10 | Searle & Co | Hydroxylated derivatives of 2, 4b-di-methyl-2-hydroxy-7-oxopolyhydrophenanthrene-1-propionic acid-delta-lactones |
| US2837464A (en) * | 1955-01-11 | 1958-06-03 | Schering Corp | Process for production of dienes by corynebacteria |
| US2983754A (en) * | 1955-01-24 | 1961-05-09 | Merck & Co Inc | Method of preparing dodecahydrophenanthrene compounds |
| US2755289A (en) * | 1955-03-17 | 1956-07-17 | Searle & Co | Anhydro derivatives of 2, 4b-dimethyl-2-hydroxy-4, 7-dioxo-1, 2, 3, 4, 4a, 4b, 5, 6,7, 9, 10, 10a-dodecahydrophenanthrene-1-propionic acid |
| US2851485A (en) * | 1955-09-02 | 1958-09-09 | Searle & Co | 7-alkanoyl derivatives of podocarpic acid |
| US2946807A (en) * | 1955-10-27 | 1960-07-26 | Olin Mathieson | 11-oxygenated-1-dehydrotestololactones |
| US2888384A (en) * | 1955-11-21 | 1959-05-26 | Upjohn Co | Process for the production of 10-hydroxy-19-nortestosterone by rhizopus |
| US2955075A (en) * | 1957-04-15 | 1960-10-04 | Olin Mathieson | Synthesis of steroids by cylindrocarpon radicicola |
-
1962
- 1962-01-11 US US165657A patent/US3174982A/en not_active Expired - Lifetime
-
1963
- 1963-01-08 BR BR145953/63A patent/BR6345953D0/en unknown
- 1963-01-09 GB GB998/63A patent/GB1012491A/en not_active Expired
- 1963-01-11 DE DEO9180A patent/DE1191371B/en active Pending
- 1963-04-08 FR FR930742A patent/FR2554M/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| US3174982A (en) | 1965-03-23 |
| BR6345953D0 (en) | 1973-05-08 |
| GB1012491A (en) | 1965-12-08 |
| FR2554M (en) | 1964-05-25 |
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